Jorg Goronzy

Publication Details

  • ERK-Dependent T Cell Receptor Threshold Calibration in Rheumatoid Arthritis JOURNAL OF IMMUNOLOGY Singh, K., Deshpande, P., Pryshchep, S., Colmegna, I., Liarski, V., Weyand, C. M., Goronzy, J. J. 2009; 183 (12): 8258-8267

    Abstract:

    Immune responses to citrullinated neoantigens and clinical efficacy of costimulation blockade indicate a general defect in maintaining T cell tolerance in rheumatoid arthritis (RA). To examine whether TCR threshold calibration contributes to disease pathogenesis, signaling in RA T cells was quantified. RA patients had a selective increase in ERK phosphorylation compared with demographically matched controls due to a mechanism distal of Ras activation. Increased ERK responses included naive and memory CD4 and CD8 T cells and did not correlate with disease activity. The augmented ERK activity delayed SHP-1 recruitment to the TCR synapse and sustained TCR-induced Zap70 and NF-kappaB signaling, facilitating responses to suboptimal stimulation. Increased responsiveness of the ERK pathway was also a characteristic finding in the SKG mouse model of RA where it preceded clinical symptoms. Treatment with subtherapeutic doses of a MEK-1/2 inhibitor delayed arthritis onset and reduced severity, suggesting that increased ERK phosphorylation predisposes for autoimmunity and can be targeted to prevent disease.

    View details for DOI 10.4049/jimmunol.0901784

    View details for Web of Science ID 000272861300071

    View details for PubMedID 20007589

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